Abstract
Lymphodepletion strategies are used in the setting of transplantation (including bone marrow, hematopoietic cell, and solid organ) to create space or to prevent allograft rejection and graft versus host disease. Following lymphodepletion, there is an excess of IL-7 available, and T cells that escape depletion respond to this cytokine undergoing accelerated proliferation. Moreover, this environment promotes the skew of T cells to a Th1 pro-inflammatory phenotype. Existing immunosuppressive regimens fail to control this homeostatic proliferative (HP) response, and thus the development of strategies to successfully control HP while sparing T cell reconstitution (providing a functioning immune system) represents a significant unmet need in patients requiring lymphodepletion. Multipotent adult progenitor cells (MAPC®) have the capacity to control T cell proliferation and Th1 cytokine production. Herein, this study shows that MAPC cells suppressed anti-thymocyte globulin-induced cytokine production but spared T cell reconstitution in a pre-clinical model of lymphodepletion. Importantly, MAPC cells administered intraperitoneally were efficacious in suppressing interferon-γ production and in promoting the expansion of regulatory T cells in the lymph nodes. MAPC cells administered intraperitoneally accumulated in the omentum but were not present in the spleen suggesting a role for soluble factors. MAPC cells suppressed lymphopenia-induced cytokine production in a prostaglandin E2-dependent manner. This study suggests that MAPC cell therapy may be useful as a novel strategy to target lymphopenia-induced pathogenic T cell responses in lymphodepleted patients.
Highlights
Despite the significant progress made in solid organ transplantation (SOT) over the past century, allo-immunity remains the greatest barrier to successful graft survival
It is well established that IL-7 is an important stimulus for the homeostatic expansion of T cells, and we have previously shown that multipotent adult progenitor cells (MAPC) cells suppress the activation of T cells in response to IL-7 in vitro [28]
We have previously shown that human MAPC cells suppress IL-7-driven proliferation and activation of T cells in vitro [28], and so this study sought to build on that data, by translating the findings to an in vivo, translationally relevant setting
Summary
Despite the significant progress made in solid organ transplantation (SOT) over the past century, allo-immunity remains the greatest barrier to successful graft survival. In the context of BMT or HCT, T cell depletion strategies are used to create space [5] While these therapies have been highly effective at reducing acute rejection and supporting engraftment in the context of BMT or HCT, significant morbidity is associated with homeostatic T cell proliferation that ensues following lymphodepletion [6,7,8,9,10]. These immunosuppressive drugs that target T cell proliferation are highly toxic and non-specific, leaving patients on long-term regimens vulnerable to kidney failure, infection, and malignancies [11]. The development of safer and more effective immunosuppressive regimens is urgently required for transplant patients
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